Skip to main content
Top
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Hepatocellular Carcinoma | Research

TRMT6 promotes hepatocellular carcinoma progression through the PI3K/AKT signaling pathway

Authors: Yanqing Ye, Maosheng Liu, Fengfei Wu, Shiyu Ou, Weidong Wang, Jieying Fei, Fang Xie, Lan Bai

Published in: European Journal of Medical Research | Issue 1/2023

Login to get access

Abstract

Background

Hepatocellular carcinoma is one of the most common and deadly cancers. The aim of this study was to elucidate the role of tRNA methyltransferase 6 (TRMT6) during HCC progression.

Methods

The role of TRMT6 in the progression and prognosis of HCC was confirmed by analysis of online databases and clinical human samples. The effects of up-regulation or down-regulation of TRMT6 on HCC cell proliferation and PI3K/AKT pathway-related protein expressions were verified. The molecular mechanism was investigated in vivo by constructing subcutaneous xenograft tumor model.

Results

TRMT6 was overexpressed in HCC tissues and associated with Tumour-Node-Metastasis (TNM) stage, primary tumor (T) and regional lymph node (N) classification. TRMT6 expressions in HCC cell lines were higher than that in normal liver cell. TRMT6 overexpression can promote HCC cell proliferation, increase the number of S phase cells. Interference with TRMT6 reduced the PI3K/AKT pathway-related protein expressions, and was reversed by the addition of IGF1. Interference with TRMT6 inhibited tumor growth in vivo and was related to PI3K/AKT pathway.

Conclusions

Overexpression of TRMT6 promote HCC cell proliferation in vivo and in vitro through PI3K/AKT/mTOR axis, which provides a potential choice for the treatment of HCC in clinical practice.
Appendix
Available only for authorised users
Literature
1.
go back to reference Ko KL, Mak LY, Cheung KS, Yuen MFJFR. Hepatocellular carcinoma: recent advances and emerging medical therapies. F1000Res. 2020;9:620.CrossRef Ko KL, Mak LY, Cheung KS, Yuen MFJFR. Hepatocellular carcinoma: recent advances and emerging medical therapies. F1000Res. 2020;9:620.CrossRef
3.
go back to reference Rimassa L, Pr Essiani T, Merle PJLC. Systemic treatment options in hepatocellular carcinoma. Liver Cancer. 2019;8:1–20.CrossRef Rimassa L, Pr Essiani T, Merle PJLC. Systemic treatment options in hepatocellular carcinoma. Liver Cancer. 2019;8:1–20.CrossRef
4.
go back to reference Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.CrossRef Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.CrossRef
5.
go back to reference Liang Y, Liu ZSG. Ultrasound reverses adriamycin-resistance in non-small cell lung cancer via positive regulation of BRAF-activated non-coding RNA (BANCR) expression. Clin Sur Res Commun. 2017;1:18–23.CrossRef Liang Y, Liu ZSG. Ultrasound reverses adriamycin-resistance in non-small cell lung cancer via positive regulation of BRAF-activated non-coding RNA (BANCR) expression. Clin Sur Res Commun. 2017;1:18–23.CrossRef
6.
go back to reference Michalak EM, Burr ML, Bannister AJ, Dawson MAJNRMCB. The roles of DNA, RNA and histone methylation in ageing and cancer. Nat Rev Mol Cell Bio. 2019;20:573–89.CrossRef Michalak EM, Burr ML, Bannister AJ, Dawson MAJNRMCB. The roles of DNA, RNA and histone methylation in ageing and cancer. Nat Rev Mol Cell Bio. 2019;20:573–89.CrossRef
7.
go back to reference Jurga S, Barciszewski J. The DNA, RNA, and histone methylomes. Cham: Springer International Publishing; 2019.CrossRef Jurga S, Barciszewski J. The DNA, RNA, and histone methylomes. Cham: Springer International Publishing; 2019.CrossRef
8.
go back to reference Czerwoniec A, Dunin-Horkawicz S, Purta E, Kaminska KH, Kasprzak JM, Bujnicki JM, et al. MODOMICS: a database of RNA modification pathways 2008 update. Nucleic Acids Res. 2009;37:D118–21.CrossRef Czerwoniec A, Dunin-Horkawicz S, Purta E, Kaminska KH, Kasprzak JM, Bujnicki JM, et al. MODOMICS: a database of RNA modification pathways 2008 update. Nucleic Acids Res. 2009;37:D118–21.CrossRef
9.
go back to reference Cantara WA, Crain PF, Rozenski J, McCloskey JA, Harris KA, Zhang X, et al. The RNA Modification Database, RNAMDB: 2011 update. Nucleic Acids Res. 2011;39:D195-201.CrossRef Cantara WA, Crain PF, Rozenski J, McCloskey JA, Harris KA, Zhang X, et al. The RNA Modification Database, RNAMDB: 2011 update. Nucleic Acids Res. 2011;39:D195-201.CrossRef
10.
go back to reference Mark HJNAR. Post-transcriptional nucleotide modification and alternative folding of RNA. Nucleic Acids Res. 2006;34:721–33.CrossRef Mark HJNAR. Post-transcriptional nucleotide modification and alternative folding of RNA. Nucleic Acids Res. 2006;34:721–33.CrossRef
11.
go back to reference Yu D, Kaur G, Blumenthal RM, Zhang X. Cheng XJJoBC Enzymatic characterization of three human RNA adenosine methyltransferases reveals diverse substrate affinities and reaction optima. J Biol Chem. 2021;296: 100270.CrossRef Yu D, Kaur G, Blumenthal RM, Zhang X. Cheng XJJoBC Enzymatic characterization of three human RNA adenosine methyltransferases reveals diverse substrate affinities and reaction optima. J Biol Chem. 2021;296: 100270.CrossRef
13.
go back to reference Kim EY, Jung JY, Kim A, Kim K, Chang YSJBC. Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer. BMC Cancer. 2017;17:467.CrossRef Kim EY, Jung JY, Kim A, Kim K, Chang YSJBC. Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer. BMC Cancer. 2017;17:467.CrossRef
14.
go back to reference Pavon-Eternod M, Gomes S, Geslain R, Dai Q, Rosner MR, Pan T. tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. 2009;37:7268–80.CrossRef Pavon-Eternod M, Gomes S, Geslain R, Dai Q, Rosner MR, Pan T. tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. 2009;37:7268–80.CrossRef
15.
go back to reference Pavon-Eternod M, Gomes S, Rosner MR, Pan T. Overexpression of initiator methionine tRNA leads to global reprogramming of tRNA expression and increased proliferation in human epithelial cells. RNA. 2013;19:461–6.CrossRef Pavon-Eternod M, Gomes S, Rosner MR, Pan T. Overexpression of initiator methionine tRNA leads to global reprogramming of tRNA expression and increased proliferation in human epithelial cells. RNA. 2013;19:461–6.CrossRef
16.
go back to reference Li X, Xiong X, Zhang M, Wang K, Yi CJMC. Base-resolution mapping reveals distinct m(1)a methylome in nuclear- and mitochondrial-encoded transcripts. Mol Cell. 2017;68:993.CrossRef Li X, Xiong X, Zhang M, Wang K, Yi CJMC. Base-resolution mapping reveals distinct m(1)a methylome in nuclear- and mitochondrial-encoded transcripts. Mol Cell. 2017;68:993.CrossRef
17.
go back to reference Schraga SJR. M1A within cytoplasmic mRNAs at single nucleotide resolution a reconciled transcriptome wide map. RNA. 2018;24(11):067348118. Schraga SJR. M1A within cytoplasmic mRNAs at single nucleotide resolution a reconciled transcriptome wide map. RNA. 2018;24(11):067348118.
18.
go back to reference Shi L, Yang XM, Tang DD, Liu G, Song DK. Expression and significance of m1A transmethylase, hTrm6p/hTrm61p and its related gene hTrm6/hTrm61 in bladder urothelial carcinoma. Am J Cancer Res. 2014;5:2169. Shi L, Yang XM, Tang DD, Liu G, Song DK. Expression and significance of m1A transmethylase, hTrm6p/hTrm61p and its related gene hTrm6/hTrm61 in bladder urothelial carcinoma. Am J Cancer Res. 2014;5:2169.
19.
go back to reference Nepomnyashchaya EM, Shaposhnikov AV, Yurieva EA. Hepatocellular carcinoma: new provisions of the WHO classification 2019. Arkh Patol. 2020;82:36–40.CrossRef Nepomnyashchaya EM, Shaposhnikov AV, Yurieva EA. Hepatocellular carcinoma: new provisions of the WHO classification 2019. Arkh Patol. 2020;82:36–40.CrossRef
20.
go back to reference Xin Xu, Wei T, Zhong W, Zhu Z, Liu F, Li Q. IL-17 regulates the expression of major histocompatibility complex II and VEGF in DLBCL mice on tumor growth. Aging Pathobio Therap. 2020;2:96–100.CrossRef Xin Xu, Wei T, Zhong W, Zhu Z, Liu F, Li Q. IL-17 regulates the expression of major histocompatibility complex II and VEGF in DLBCL mice on tumor growth. Aging Pathobio Therap. 2020;2:96–100.CrossRef
21.
go back to reference Zhao Y, Zhao Q, Kaboli PJ, Shen J, Li M, Wu X, et al. m1A regulated genes modulate PI3K/AKT/mTOR and ErbB pathways in gastrointestinal cancer. Translational Oncol. 2019;12:1323–33.CrossRef Zhao Y, Zhao Q, Kaboli PJ, Shen J, Li M, Wu X, et al. m1A regulated genes modulate PI3K/AKT/mTOR and ErbB pathways in gastrointestinal cancer. Translational Oncol. 2019;12:1323–33.CrossRef
22.
go back to reference Shi L, Yang X-M, Tang D-D, Liu G, Yuan P, Yang Y, et al. Expression and significance of m1A transmethylase, hTrm6p/hTrm61p and its related gene hTrm6/hTrm61 in bladder urothelial carcinoma. Am J Cancer Res. 2015;5:2169–79. Shi L, Yang X-M, Tang D-D, Liu G, Yuan P, Yang Y, et al. Expression and significance of m1A transmethylase, hTrm6p/hTrm61p and its related gene hTrm6/hTrm61 in bladder urothelial carcinoma. Am J Cancer Res. 2015;5:2169–79.
23.
go back to reference Erstad DJ, Fuchs BC, Tanabe KK. Molecular signatures in hepatocellular carcinoma: a step toward rationally designed cancer therapy. Cancer. 2018;124:3084–104.CrossRef Erstad DJ, Fuchs BC, Tanabe KK. Molecular signatures in hepatocellular carcinoma: a step toward rationally designed cancer therapy. Cancer. 2018;124:3084–104.CrossRef
24.
go back to reference Ally A, Balasundaram M, Carlsen R, Chuah E, Clarke A, Dhalla N, et al. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169:1327.CrossRef Ally A, Balasundaram M, Carlsen R, Chuah E, Clarke A, Dhalla N, et al. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169:1327.CrossRef
26.
go back to reference Liu F, Clark W, Luo G, Wang X, He CJC. ALKBH1-mediated tRNA demethylation regulates translation. Cell. 2016;167:816.CrossRef Liu F, Clark W, Luo G, Wang X, He CJC. ALKBH1-mediated tRNA demethylation regulates translation. Cell. 2016;167:816.CrossRef
27.
go back to reference Safra M, Sas-Chen A, Nir R, Winkler R, Nachshon A, Bar-Yaacov D, et al. A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature. 2017;551:251–5.CrossRef Safra M, Sas-Chen A, Nir R, Winkler R, Nachshon A, Bar-Yaacov D, et al. A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature. 2017;551:251–5.CrossRef
28.
go back to reference Endres L, Fasullo M, Rose RJFMC. tRNA modification and cancer: potential for therapeutic prevention and intervention. Future Med Chem. 2019;11:885–900.CrossRef Endres L, Fasullo M, Rose RJFMC. tRNA modification and cancer: potential for therapeutic prevention and intervention. Future Med Chem. 2019;11:885–900.CrossRef
29.
go back to reference Emma A, Matteo AP. Giovanni LJJoC role of urinary biomarkers in the diagnosis of adenoma and colorectal cancer: a systematic review and meta-analysis. J Cancer. 2016;7:1984–2004.CrossRef Emma A, Matteo AP. Giovanni LJJoC role of urinary biomarkers in the diagnosis of adenoma and colorectal cancer: a systematic review and meta-analysis. J Cancer. 2016;7:1984–2004.CrossRef
30.
go back to reference Zhao Y, Zhao Q, Kaboli PJ, Shen J, Xiao ZJTO. m1A regulated genes modulate PI3K/AKT/mTOR and ErbB pathways in gastrointestinal cancer. Transl Oncol. 2019;12:1323–33.CrossRef Zhao Y, Zhao Q, Kaboli PJ, Shen J, Xiao ZJTO. m1A regulated genes modulate PI3K/AKT/mTOR and ErbB pathways in gastrointestinal cancer. Transl Oncol. 2019;12:1323–33.CrossRef
31.
go back to reference Wang Y, Huang Q, Deng T, Li BH, Ren XQ. Clinical significance of TRMT6 in hepatocellular carcinoma: a bioinformatics-based study. Med Sci Monit. 2019;25:3894–901.CrossRef Wang Y, Huang Q, Deng T, Li BH, Ren XQ. Clinical significance of TRMT6 in hepatocellular carcinoma: a bioinformatics-based study. Med Sci Monit. 2019;25:3894–901.CrossRef
32.
go back to reference Yeon SY, Jo YS, Choi EJ, Kim MS, Yoo NJ, Lee SH. Frameshift mutations in repeat sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 genes in colon cancers. Pathol Oncol Res. 2018;24:617–22.CrossRef Yeon SY, Jo YS, Choi EJ, Kim MS, Yoo NJ, Lee SH. Frameshift mutations in repeat sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 genes in colon cancers. Pathol Oncol Res. 2018;24:617–22.CrossRef
33.
go back to reference Noorolyai S, Shajari N, Baghbani E, Sadreddini S, Baradaran B. The relation between PI3K/AKT signalling pathway and cancer. Gene. 2019;698:120–8.CrossRef Noorolyai S, Shajari N, Baghbani E, Sadreddini S, Baradaran B. The relation between PI3K/AKT signalling pathway and cancer. Gene. 2019;698:120–8.CrossRef
34.
go back to reference Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550–62.CrossRef Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550–62.CrossRef
Metadata
Title
TRMT6 promotes hepatocellular carcinoma progression through the PI3K/AKT signaling pathway
Authors
Yanqing Ye
Maosheng Liu
Fengfei Wu
Shiyu Ou
Weidong Wang
Jieying Fei
Fang Xie
Lan Bai
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-022-00951-1

Other articles of this Issue 1/2023

European Journal of Medical Research 1/2023 Go to the issue